In this project, the role of Fe will be examined in the generation of reactive hydroxy radicals by redox-cycling of estrogens and its role in estrogen-induced carcinogenesis. In westernized societies, excess iron is taken in via dietary supplements. However, an elevated risk of cancer is associated in humans with high body iron stores. The hypothesis is that superoxide radicals, generated by metabolic redox cycling of catecholestrogen metabolites, reduce Fe3+, stored in ferritin, to Fe2+ which is released from ferritin and in turn reduces H2O2 to OH (Fenton reaction). The goal of this study is to demonstrate that iron is mobilized from ferritin during metabolic redox cycling of estrogens and that it supports hydroxy radical generation and DNA damage during estrogen-induced carcinogenesis. This hypothesis will be tested by examining 1. release of Fe2+ from ferritin/Fe3+ by redox cycling of estrogens in vitro. 2. the possible accumulation of chelatable Fe2+ in kidney of estrogen-treated hamsters prior to the appearance of renal tumors, but not in liver in which tumors are not induced by this treatment. 3. Fe2+ release in kidney of estrogen-treated hamsters as a redox cycling-dependent process (by using inhibitors of cytochrome P450) and not a receptor-mediated process (by using antiestrogens) 4. the incidence of estrogen-induced kidney tumors in hamsters treated with estradiol and diets containing very low, medium or high levels of iron.